Ropinirole-Containing Adhesive Patch

ABSTRACT

Provided is an adhesive patch containing ropinirole serving as a therapeutic drug for Parkinson&#39;s disease, with the ropinirole used being free ropinirole (ropinirole in free form) added to an adhesive base, wherein the patch exhibits favorable drug permeability and excellent drug stability. Also provided is a transdermal absorption patch using, as an adhesive base, an acrylic-based adhesive having no specific carboxyl group and having a hydroxyl group or a pyrrolidone group, with the patch including free ropinirole added to the adhesive base. Further provided is a ropinirole-containing transdermal absorption patch including a transdermal absorption promoting agent.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/362,001, filed May 30, 2014, which is a 371 of InternationalApplication No. PCT/JP2012/081083, the disclosures of which areexpressly incorporated by reference herein.

TECHNICAL FIELD

The present invention relates to an adhesive patch that uses, as a mainbase, an acrylic-based adhesive having a hydroxyl group or a pyrrolidonegroup and having no carboxyl group and contains free form of ropinirolein the base.

BACKGROUND ART

Ropinirole was developed as a dopamine agonist and is used for treatmentof Parkinson's disease, and oral preparations of ropinirole aredistributed in the market. There have been attempts to formulateropinirole into patches (Patent Documents 1 and 2).

One advantage of the patches is that the preparations can be easilyremoved when a side effect occurs.

At present, ropinirole distributed in the market is its acid additionsalt (specifically, ropinirole hydrochloride) because of its stabilityand handleability, and it is contemplated that transdermal absorptionpreparations are produced using the acid addition salt of ropinirole(Patent Document 3). However, generally, a transdermal absorptionpreparation using a drug in the form of acid addition salt has adrawback in that transdermal absorbability is much lower than that whena free drug (drug in free form) is used.

When a dehydrochlorinating agent is used to convert the acid additionsalt of ropinirole to free ropinirole within the preparation, the amountof the drug contained in the adhesive base is limited, and the acidaddition salt is not completely converted to free ropinirole, so thattransdermal absorbability may not be increased so much. In addition, ametal salt may precipitate in the adhesive base, causing problems suchas deterioration of the physical properties of the patch and skinirritation by the metal salt.

PRIOR ART LIST Patent Document

Patent Document 1: Japanese Translation of PCT International ApplicationNo. 2001-518058

Patent Document 2: Japanese Translation of PCT International ApplicationNo. Hei 11-506462

Patent Document 3: International Publication WO2009/107478

DISCLOSURE OF INVENTION Problem to be Solved by the Invention

In view of the foregoing problems, the present invention provides anadhesive patch containing free ropinirole (ropinirole in free form) inan adhesive base with the patch exhibiting favorable drug permeabilityand high drug stability.

Means for Solving the Problem

To solve the above problems, the present inventors have conductedextensive studies and confirmed that, when free ropinirole is added to aspecific acrylic-based adhesive in consideration of the chemicalcharacteristics of ropinirole, favorable drug permeability and high drugstability can be obtained. Thus, the present invention has beencompleted.

Accordingly, as a basic aspect the present invention is a transdermalabsorption patch including: an acrylic-based adhesive serving as anadhesive base, having no carboxyl group and having a hydroxyl group or apyrrolidone group; and free ropinirole added to the adhesive base.

As a specific aspect the present invention is a transdermal absorptionpatch including: an acrylic-based adhesive serving as an adhesive base,containing no cross-linking agent, having no carboxyl group, and havinga hydroxyl group or a pyrrolidone group; and free ropinirole added tothe adhesive base.

As another specific aspect the present invention is a transdermalabsorption patch including: an acrylic-based adhesive serving as anadhesive base, containing no cross-linking agent, having no carboxylgroup, and having a hydroxyl group or a pyrrolidone group; and freeropinirole added to the adhesive base; wherein the transdermalabsorption patch further includes a transdermal absorption enhanceradded thereto.

As a specific aspect, the present invention is the transdermalabsorption patch wherein the acrylic-based adhesive is a 2-ethylhexylacrylate/vinyl acetate/2-hydroxyethyl acrylate copolymer.

As another specific aspect the present invention is the transdermalabsorption patch wherein the acrylic-based adhesive is a 2-ethylhexylacrylate/vinylpyrrolidone copolymer.

More specifically, the present invention is the transdermal absorptionpatch wherein the transdermal absorption enhancer is one or two or morekinds selected from triethyl citrate, glycerin, sorbitan monolaurate,oleyl alcohol, and isopropyl myristate.

More specifically, the present invention is the transdermal absorptionpatch wherein the transdermal absorption enhancer in the acrylic-basedadhesive is one or two or more kinds selected from lauryl alcohol andisopropyl myristate.

Still another specific aspect of the present invention is a transdermalabsorption patch including: an acrylic-based adhesive serving as anadhesive base, containing no cross-linking agent, having no carboxylgroup, and having a hydroxyl group or a pyrrolidone group; and freeropinirole added to the adhesive base, wherein, when a crystal seedingmethod (CS method) is preformed, a factor (C) representing the growthdegree of ropinirole crystals in the adhesive satisfies (C)≦1.

The CS method will be described later.

Effect of the Invention

According to the present invention, the transdermal absorption patchincludes: an acrylic-based adhesive serving as an adhesive base, havingno carboxyl group and having a hydroxyl group or a pyrrolidone group;and free ropinirole added to the adhesive base. By this configuration,the free ropinirole is completely dissolved in the acrylic adhesiveserving as the adhesive base, so that the patch obtained can allow hightransdermal absorbability and have excellent drug stability.

Therefore, with the transdermal absorption patch provided by the presentinvention, the free ropinirole serving as an active ingredient istransdermally absorbed from the adhesive layer in a favorable manner, sothat the transdermal absorption patch is effective for treatment ofParkinson's disease.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a micrograph showing the appearance of the surface of anadhesive base in Example 1 of the present invention during a CS methodtest immediately after the start of the test. FIG. 2 is a micrographshowing the appearance of the surface of the adhesive base in Example 1of the present invention after completion of the CS method test.

FIG. 3 is a micrograph showing the appearance of the surface of anadhesive base in Reference Example 2 during the CS method testimmediately after the start of the test.

FIG. 4 is a micrograph showing the appearance of the surface of theadhesive base in Reference Example 2 after completion of the CS methodtest.

FIG. 5 is a view showing the results of a skin permeation test in TestExample 4-(1) of the present invention.

FIG. 6 is a view showing the results of the skin permeation test in TestExample 4-(2) of the present invention.

FIG. 7 is a view showing the results of the skin permeation test in TestExample 4-(3) of the present invention.

MODES FOR CARRYING OUT THE INVENTION

A basic aspect of the present invention is a transdermal absorptionpatch in which free ropinirole is added to a specific acrylic-basedadhesive base.

No particular limitation is imposed on the amount of free ropiniroleadded to the transdermal absorption patch provided by the presentinvention, so long as the patch can be prepared. The amount of freeropinirole added is preferably within the range of 3 to 30% by weight,more preferably 7 to 20% by weight, and still more preferably 8 to 15%by weight based on the weight of the entire composition of the adhesivelayer.

If the amount of free ropinirole added is less than 3% by weight,transdermal absorbability is insufficient. If the amount added is 30% byweight or more, the physical properties of the patch are impaired, andalso such an amount is economically disadvantageous and is notpreferred.

The acrylic-based adhesive serving as the main base of the transdermalabsorption patch provided by the present invention is preferably anacrylic-based adhesive having a hydroxyl group or a pyrrolidone groupand having no carboxyl group.

In the present invention, it is preferable that no cross-linking agentbe added to the acrylic-based adhesive. The addition of a cross-linkingagent tends to facilitate the decomposition reaction of ropiniroleserving as the main active ingredient, to cause a reduction in theamount of the main active ingredient, and to facilitate generation ofdecomposition products. However, when the physical properties of theadhesive layer cannot be maintained unless a cross-linking agent isadded, it is necessary to take measures for suppressing the reaction ofthe drug and the cross-linking agent.

In view of the above, it is preferable in the present invention that theacrylic-based adhesive used be an acrylic-based adhesive containing nocross-linking agent or an acrylic-based adhesive having enhancedcohesion with no cross-linking agent added thereto.

The acrylic-based adhesive having no carboxyl group and having ahydroxyl group is, for example, an acrylic-based adhesive famed from analkyl (meth)acrylate having 1 to 18 carbon atoms and a monomer having ahydroxyl group. No particular limitation is imposed on the alkyl(meth)acrylate, and examples thereof may include alkyl (meth)acrylatessuch as butyl (meth)acrylate, isobutyl (meth)acrylate, octyl(meth)acrylate, 2-ethylhexyl (meth)acrylate, isooctyl (meth)acrylate,decyl (meth)acrylate, isodecyl (meth)acrylate, lauryl (meth)acrylate,stearyl (meth)acrylate, and ethyl (meth)acrylate. These may be usedsingly or in combination of two or more. Examples of the monomer havinga hydroxyl group may include hydroxyalkyl (meth)acrylates such as2-hydroxyethyl (meth)acrylate and hydroxypropyl (meth)acrylate.

As the acrylic-based adhesive having no carboxyl group and having ahydroxyl group, examples may include 2-ethylhexyl acrylate/vinylacetate/2-hydroxyethyl acrylate/glycidyl methacrylate copolymer, and2-ethylhexyl acrylate/vinyl acetate/2-hycroxyethyl acrylate copolymer.Specifically, for example, Duro-tak acrylic adhesives having a hydroxylgroup and available from National Starch and Chemical Company (grades:Duro-tak 87-2510, Duro-tak 87-2516, Duro-tak 87-4287, Duro-tak 87-2287,etc.) can be preferably used. Of these, Duro-tak 87-4287, which is anadhesive that shows sufficiently high cohesion with no cross-linkingagent added, is more preferable.

For example, an acrylic-based adhesive formed from an alkyl(meth)acrylate having 1 to 18 carbon atoms and a monomer having apyrrolidone group is used as the acrylic-based adhesive used in thepresent invention that has no carboxyl group and has a pyrrolidonegroup. No particular limitation is imposed on the alkyl (meth)acrylate,and examples thereof may include alkyl (meth)acrylates such as butyl(meth)acrylate, isobutyl (meth) acrylate, octyl (meth) acrylate,2-ethylhexyl (meth) acrylate, isooctyl (meth)acrylate, decyl(meth)acrylate, isodecyl (meth)acrylate, lauryl (meth)acrylate, stearyl(meth)acrylate, and ethyl (meth)acrylate. These may be used singly or incombination of two or more. Examples of the monomer having a pyrrolidonegroup and copolymerizable with the alkyl (meth)acrylate may includeN-vinyl-2-pyrrolidone and methylvinylpyrrolidone. Preferred examples ofthe adhesive may include a 2-ethylhexyl acrylate/vinylpyrrolidonecopolymer.

When an acrylic-based adhesive having no hydroxyl group and nopyrrolidone group is used, the high solubility of free ropiniroleserving as the medicinal ingredient cannot be obtained.

When an acrylic-based adhesive having a carboxyl group is used,ropinirole serving as the main active ingredient is not released fromthe adhesive, so that high transdermal absorbability cannot be obtained.

In the transdermal absorption patch provided by the present invention,the average molecular weight (MW) of the acrylic-based adhesive used ispreferably 300,000 or more and more preferably 400,000 or more.

The content of the acrylic-based adhesive used is preferably 30 to 98%by weight and more preferably 50 to 95% by weight based on the mass ofthe entire composition of the adhesive layer.

The transdermal absorption patch of the present invention may contain atransdermal absorption enhancer. Examples of the transdermal absorptionenhancer may include methyl laurate, hexyl laurate, triethyl citrate,isopropyl myristate (hereinafter abbreviated as IPM), myristylmyristate, octyldodecyl myristate, cetyl palmitate, triacetin, cetyllactate, lauryl lactate, methyl salicylate, glycol salicylate, ethyleneglycol salicylate, diethyl sebacate, diisopropyl sebacate, medium-chainfatty acid triglyceride, lauryl alcohol, stearyl alcohol, isostearylalcohol, myristyl alcohol, oleyl alcohol, cetanol, glycerinmonocaprylate, glycerin monolaurate, glycerin monooleate, sorbitanmonolaurate, sorbitan monooleate, sucrose monolaurate, polysorbate 20,propylene glycol monolaurate, polyethylene glycol monostearate,lauromacrogol, HCO-60, lauric acid diethanolamide,N-methyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 5-methyl-2-pyrrolidone,N-octyl-2-pyrrolidone, dimethyl sulfoxide, glycerin, sorbitanmonolaurate, and crotamiton.

Of these, one or two or more kinds selected from triethyl citrate,glycerin, oleyl alcohol, sorbitan monolaurate, and isopropyl myristateare preferably used, and one or two or more kinds selected from oleylalcohol and isopropyl myristate are more preferred.

The amount added of the transdermal absorption enhancer is 0.1 to 20% byweight, preferably 0.1 to 10% by weight, and more preferably 2 to 10% byweight based on the weight of the entire composition of the adhesivelayer. If the amount added of the absorption enhancer is less than 0.1weight, the transdermal absorbability is not improved. On the otherhand, if the amount added of the transdermal absorption enhancer is morethan 20 weight, the physical properties of the preparation deteriorate.

Preferably, the transdermal absorption patch provided by the presentinvention contains an antioxidant. Preferred examples of the antioxidantmay include BHT (butylhydroxytoluene), concentrated mixed tocopherol,tocopherol, tocopherol acetate, 2-mercaptobenzimidazole,pentaerythrityl-tetrakis, and ascorbic acid. Of these, BHT andtocopherol are particularly preferred.

The amount added of the antioxidant is 0.1 to 5% by weight andpreferably 0.1 to 2% by weight based on the mass of the entirecomposition of the adhesive layer.

If necessary, the transdermal absorption patch provided by the presentinvention may contain liquid components such as a softening agent and aresolvent.

Examples of the softening agent may include polyisobutylene, polybutene,lanolin, castor oil, almond oil, olive oil, camellia oil, persic oil,peanut oil, process oil, extender oil, and liquid paraffin.

Examples of the resolvent may include: fatty acid esters such asisopropyl myristate, diethyl sebacate, diisopropyl sebacate, diisopropyladipate, and isopropyl palmitate; and polyols such as propylene glycol,polyethylene glycol, butylene glycol, and glycerin.

Moreover, various base components used in ordinary external preparationscan be used for the transdermal absorption patch of the presentinvention, so long as the base components have no influence on the othercomponents.

No particular limitation is imposed on these base components, andexamples thereof may include: water-soluble polymers such aspolyvinylpyrrolidone, polyvinyl alcohol, and polyacrylic acid; cellulosederivatives such as ethyl cellulose, hydroxypropyl cellulose, andhydroxypropyl methyl cellulose; silicon compounds such as silicic acidanhydride and light silicic acid anhydride; and inorganic fillers suchas zinc oxide, aluminum oxide, titanium dioxide, silica, magnesiumoxide, iron oxide, and stearic acid.

Moreover, a preservative, an algefacient, an antimicrobial, a flavoringagent, a colorant, etc. may be added as needed.

No particular limitation is imposed on the support for the transdermalabsorption patch provided by the present invention, and any ofstretchable and non-stretchable supports may be used.

More specifically, the support used may be any of paper materials andfilms, sheets, stacks thereof, porous membranes, foamed materials, wovenfabrics, and nonwoven fabrics formed from synthetic resins such aspolyethylene terephthalate, polyethylene, polypropylene, polybutadiene,ethylene-vinyl acetate copolymers, polyvinyl chloride, polyester, nylon,and polyurethane.

A release liner formed of, for example, polyethylene terephthalate,polypropylene, or paper may be used, and polyethylene terephthalate isparticularly preferred.

If necessary, the release liner may be subjected to silicon treatment toobtain optimal peel force.

A deoxidizer may be allowed to coexist with the transdermal absorptionpatch of the present invention. The deoxidizer used is preferably adeoxidizer famed from iron as a raw material or a deoxidizer formed froma nonferrous metal as a raw material. Examples of the method of allowingthe deoxidizer to coexist include a method in which the deoxidizer isdirectly sealed in a package bag and a method in which a package bagformed from a stack including a deoxidizer film is used.

In the transdermal absorption patch of the present invention, thestability of ropinirole in the adhesive base can be relatively easilychecked using a crystal seeding method (CS method), which is a simplemethod of testing stability of a drug. The CS method is a test method inwhich crystals of a drug are scattered on an adhesive base and thegrowth degree of the crystals of the drug is observed to determine theshort-term stability of the drug in the adhesive base.

For the patch of the present invention, the long-term stability of thedrug in the preparation can be estimated from the results of the CSmethod. Specifically, when dissolution of the scattered drug into theadhesive base is found in the results of the

CS method or the growth of the crystals of the scattered drug is notobserved in the results, it can be judged that the possibility ofcrystallization of the drug even under long-term storage conditions islow. When the growth of the crystals of the drug is observed in the CSmethod, it is feared that crystals of the drug may precipitate in thepreparation under long-term storage conditions.

More specifically, the CS method is performed in the following manner,and the stability of the crystals of the drug in the preparation isevaluated according to the evaluation criteria described later.

<Test Procedure of CS Method>

A release film of a patch is removed. Then a support of the patch issecured to a glass slide, and this patch is used as a test specimen.Alternatively, part of the adhesive in the patch is collected, and thecollected adhesive is applied to a glass slide and used as a testspecimen.

Next, bulk powder of ropinirole is scattered directly on the adhesiveportion of the test specimen. No particular limitation is imposed on theparticle diameter of the scattered drug, but the particle diameter ofthe drug used is preferably 0.1 to 5,000 μm, in order to clearly observethe generation of crystals of the scattered drug.

The crystals of the drug immediately after they are scattered areobserved under an electron microscope (for example, a digital microscopeVHX-600 manufactured by KEYENCE), and image data inputted from theelectron microscope through an image data processing unit is outputted.

Then DSB/S, i.e., the ratio of the total area of the crystals of thescattered drug (the projected area from above: DSB) per unit area (S) ofthe adhesive, is determined on the basis of the outputted image data.

After the test specimen is left to stand at room temperature for 3 to 10days, the test specimen is observed under the electron microscope in thesame manner as immediately after the crystals are scattered. Then DSA/S,i.e., the ratio of the total area of the crystals of the scattered drug(the projected area from above: DSA) per unit area (S) of the adhesive,is similarly determined.

A factor (C) representing the growth degree of the crystals of thescattered drug in each test specimen is determined from the obtainedvalues of DSB/S and DSA/S as follows.

(C)=(b)/(a)

[In the formula above,

(a): the ratio of the total area of the crystals of the scattered drug(the projected area from above: DSB) scattered in a certain area (S) onthe surface of the adhesive, i.e., DSB/S, immediately after the start ofthe test (immediately after the crystals of the drug are scattered).

(b): the ratio of the total area of the crystals of the scattered drug(the projected area from above: DSA) scattered in the certain area (S)on the surface of the adhesive, i.e., DSA/S, after completion of thetest (10 days after the crystals of the drug are scattered).]

<Evaluation Criteria>

Evaluation is made using the value of (C) obtained above according tothe evaluation criteria below.

(C)≦1:   (i)

Growth of the crystals of the drug scattered on the adhesive is notobserved, or the crystals are reduced in size.

(C) 1:   (ii)

The crystals of the drug scattered on the adhesive have grown.

An example of a method of producing the transdermal absorption patchprovided by the present invention will next be described.

Specifically, the acrylic-based adhesive, free ropinirole, and othercomponents such as an antioxidant are dissolved in a suitable solventusing a mixer to obtain an adhesive solution. The solvent used may beethyl acetate, ethanol, methanol, etc. A suitable solvent is selectedaccording to the components, and only one solvent or a combination oftwo or more solvents may be used.

Next, the thus-obtained adhesive solution is spread over a release filmor a support, and the solvent is removed by drying. Then the support andthe release film are laminated with each other, whereby a transdermalabsorption patch can be obtained.

The thickness of the adhesive layer is preferably about 30 to about 200μm and more preferably about 50 to about 100 μm.

If the thickness is less than 30 μm, the duration of release of the drugbecomes short. If the thickness is larger than 200 μm, the amount of thedrug contained in the adhesive layer becomes large, and this causes anincrease in production cost.

EXAMPLES

The present invention will next be more specifically described by way ofExamples and Comparative Examples, but the present invention is notlimited to the following Examples.

Example 1

Ethyl acetate was used as a solvent, and free ropinirole and anacrylic-based adhesive (2-ethylhexyl acrylate/vinylacetate/2-hydroxyethyl acrylate copolymer; product name: Duro-tak87-4287) were mixed using a mixer to obtain an adhesive solution.

The adhesive solution was spread over a release-treated film, and thesolvent was removed by drying to form an adhesive layer having athickness of 60 to 70 μm. Then a support was placed on the adhesivelayer to press-bond and transferred the adhesive layer, whereby a patchwas obtained.

The amounts added of the respective components (unit: % by weight) andthe mixing ratio are shown in TABLE 1.

Examples 2 to 5

Respective patches in Examples 2 to 5 having compositions shown in TABLE1 (unit: % by weight) were obtained in accordance with the productionmethod in Example 1.

Reference Examples 1 and 2

Patches in Reference Examples 1 and 2 having compositions shown in TABLE1 (unit: % by weight) were obtained in accordance with the productionmethod in Example 1.

TABLE 1 Examples Ref. Examp. 1 2 3 4 5 1 2 Free form of Ropinirole 10 8 8  5 10  5 12 BHT — 1 — — — — — Duro-tak 87-4287 ¹⁾ 90 91  92 95 — — 88Ethylhexyl acrylate/ — — — — 90 — — vinylpyrrolidone copolymer ²⁾Duro-tak 87-2516 ³⁾ — — — — — 95 — Note ¹⁾ Duro-tak 87-4287:2-ethylhexyl acrylate/vinyl acetate/2-hydroxyethyl acrylate copolymer(an acrylic-based adhesive containing no cross-linking agent, having ahydroxyl group, and having no carboxyl group) Note ²⁾ Ethylhexylacrylate/vinylpyrrolidone copolymer: an acrylic-based adhesivecontaining no cross-linking agent, having a pyrrolidone group, andhaving no carboxyl group Note ³⁾ Duro-tak 87-2516: an acrylic-basedadhesive containing a cross-linking agent, having a hydroxyl group, andhaving no carboxyl group

Examples 6 to 13

Patches in Examples 6 to 13 having compositions shown in TABLE 2 (unit:% by weight) were obtained in accordance with the production method inExample 1.

TABLE 2 Examples 6 7 8 9 10 11 12 13 Free form of Ropinirole 10 10 10 1010 12 14 12 Duro-tak 87-4287 ¹⁾ 85 85 88 85 85 83 81 83 Triethyl citrate 5 — — — — — — — Glycerin —  5 — — — — — — Sorbitan monolaurate — —  2 —— — — — Oleyl alcohol — — —  5 —  5  5 — Isopropyl myristate — — — —  5— —  5 Note ¹⁾ Duro-tak 87-4287: 2-ethylhexyl acrylate/vinylacetate/2-hydroxyethyl acrylate copolymer (an acrylic-based adhesivecontaining no cross-linking agent, having a hydroxyl group, and havingno carboxyl group)

Comparative Examples 1 and 2

Patches in respective Comparative Examples were produced in the samemanner as in Example 1 except that respective components were used inratios shown in TABLE 3 (unit: % by weight).

Comparative Example 3

With reference to a prescription and a production method in Example 3 inInternational Publication WO2009/107478, a patch in Comparative Example3 was produced. The prescription (unit: % by weight) is shown in TABLE3.

TABLE 3 Comparative Examples 1 2 3 Free form of Ropinirole 10 10 —Ropinirole hydrochloride — — 5 Sodium hydroxide — — 0.5 2-Ethylhexylacrylate/dodecyl 90 — — methacrylate copolymer⁴⁾ Duro-tak 87-2194⁵⁾ — 90— Duro-tak 87-900A⁶⁾ — — 95 Note ⁴⁾An acrylic-based adhesive containingno functional groups Note ⁵⁾Duro-tak 87-2194: an acrylic-based adhesivehaving a carboxyl group Note ⁶⁾Duro-tak 87-900A: an acrylic-basedadhesive having no hydroxyl group and no carboxyl group

Test Example 1 Examination of Stability of Drug in Preparations byCrystal Seeding Method (CS Method)

The stability of the drug in each of the preparations in exmples 1 to13, Reference Examples 1 and 2, and Comparative Examples 1 and 2 wasexamined by the CS method. The test procedure and the evaluationcriteria for the test results are shown below, and the test results areshown in TABLE 4 and 5.

The test procedure of the CS method was the same as that described abovefor the CS method.

The adhesive portion in each of the Examples and Comparative Exampleswas collected as a test sample, and the test sample was applied to aglass slide and used as a test specimen.

Observation by a microscope was performed using a digital microscope(type: KEYENCE VHX-600, magnification: 400×). The particle diameter ofthe used raw ropinirole scattered on the adhesive was 5 to 3,000 μm, andthe test was terminated 10 days after the drug was scattered.

In each TABLE, the factor (C) representing the degree of growth ofcrystals is shown as circle or cross according to the followingevaluation criteria.

◯: when (C)<1

×: when (C)>1

As can be seen from the results of the above test, in the adhesives inExamples 1 to 13 that are used as the transdermal absorption patches ofthe present invention, growth of the crystals was not observed, and itwas found that ropinirole was stably dissolved in the adhesive base.However, in the preparations in Comparative Example 1 and ReferenceExample 2, growth of the crystals was found after completion of thetest, and it was suggested that ropinirole was present in the adhesivebase in an unstable state.

TABLE 4 Reference Comparative Examples Examples Examples 1 2 3 4 5 1 2 12 Growth of Crystals ◯ ◯ ◯ ◯ ◯ ◯ X X ◯

TABLE 5 Examples 6 7 8 9 10 11 12 13 Growth of Crystals ◯ ◯ ◯ ◯ ◯ ◯ ◯ ◯

Test Example 2 Examination of Recrystallization of Drug in PreparationsStore for Long Time

Each of the patches obtained in the above Examples and ComparativeExamples was cut into a size of 2.5×2.5 cm, and the cut pieces wereindividually packaged in package bags having a polyacrylonitrileinnermost layer and stored at room temperature for 6 months. Then, foreach stored specimen, the package bag was opened, and whether or notfree ropinirole were crystallized in the adhesive was checked visually.

The results are shown in TABLE 6.

TABLE 6 Reference Comparative Examples Examples Examples 1 2 3 4 5 1 2 12 Growth of Crystals No No No No No No Yes Yes No

For the adhesives in Examples 1 to 5 that are used as the transdermalabsorption patches of the present invention, no crystallization of drugwas found. The ropinirole was sufficiently dissolved in the adhesive,and it was found that the patches using these adhesives werepreparations of the complete dissolution type.

The results of this test agree with the results of the test forexamining the short-team stability in the patches by the CS method inTest Example 1.

Test Example 3 Stability Test for Principal Agent

The patches in Example 4 and Reference Example 1 that had been storedunder the storage condition of 40° C. for one month were punched into asize of 6.25 cm² and placed in 50 mL centrifugal precipitation tubes.Tetrahydrofuran (hereinafter abbreviated as THF) was added to each tube,and ultrasonic extraction and extraction using a shaker were performed.The obtained extract was collected in a 100-mL volumetric flask, and thevolume was adjusted to 100 mL with THF.

6 mL of the extract was collected, and its volume was adjusted to 50 mLusing a 15% acetonitrile aqueous solution. Then the resultant solutionwas filtrated through a membrane filter (0.45 pμ), and the content ofropinirole was measured by HPLC.

The HPLC measurement conditions are as follows.

Column: waters spherisorb 3CN (3×150 mm)

Mobile phase: acetonitrile:water:phosphoric acid =150:850:0.85

Flow rate: 0.4 mL/min

Wavelength: 249 nm

Injection amount: 10 μL

The results are shown in TABLE 7.

The results are represented as relative values (%) with respect to theinitial amounts of ropinirole.

TABLE 7 Test Patch Example 4 Reference Example 1 Relative values (%)97.4 94.2 to initial value

As can be seen from the results in TABLE 7, it was found that thetransdermal absorption patch of the present invention is a preparationwith excellent stability of free ropinirole serving as the principalagent.

Test Example 4 Skin Permeation Test on Hairless Mice

The patches in Example 1, Examples 4 to 13, and Comparative Examples 2and 3 were subjected to an in vitro skin permeation test using skinexcised from hairless mice (HR-1, 7 week old).

The back skin of a hairless mouse was removed. The dermis was set on areceptor with its inside filled with phosphate buffered saline, and warmwater at 37° C. was refluxed through a water jacket.

Each test patch was punched into a circular shape (1.54 cm²) and appliedto the excised skin. The receptor solution was sampled at timeintervals, and the skin permeation amount of the drug was measured bythe high-performance liquid chromatography. The rate of transdermalabsorption (Flux: μg/cm²/hr) in steady state was computed from theresults of the measurement.

The test was performed for each of five combinations of test specimens[Test Examples 4-(1) to (5)] shown in TABLEs 8 to 12.

The results are shown in TABLEs 8 to 12. In TABLEs 8 to 10, the resultsare shown by the rate of transdermal absorption and the relative rate oftransdermal absorption. In TABLEs 11 and 12, the results are shown onlyby the relative ratio of transdermal absorption.

The results for Test Examples 4-(1), 4-(2), and 4-(3) are also shown inFIGS. 5 to 7.

In FIGS. 5 to 7, the results are shown as the cumulative permeationamount.

TABLE 8 Test Example 4-(1) Rate of Transdermal Relative Rate ofAbsorption Transdermal Absorption Test Patch (Flux: μg/cm²/hr) (vs.Example 1) Example 1 22.56 1.00 Compt. Example 2 2.44 0.11

TABLE 9 Test Example 4-(2) Rate of Transdermal Relative Rate ofAbsorption Transdermal Absorption Test Patch (Flux: μg/cm²/hr) (vs.Example 1) Example 1 20.58 1.00 Example 5 22.81 1.01

TABLE 10 Test Example 4-(3) Rate of Transdermal Relative Rate ofAbsorption Transdermal Absorption Test Patch (Flux: μg/cm²/hr) (vs.Example 1) Example 4 7.08 1.00 Compt. Example 3 1.87 0.26

TABLE 11 Relative Rate of Transdermal Absorption Test Patch (vs.Example 1) Example 1 1.00 Example 6 1.10 Example 7 1.45 Example 8 1.39Example 9 1.68 Example 10 1.68

TABLE 12 Relative Rate of Transdermal Absorption Test Patch (vs. Example3) Example 3 1.00 Example 11 1.78 Example 12 2.09 Example 13 1.40

As can be seen from the results shown in the figures, the transdermalabsorption patches of the present invention (Examples 1 and 4 to 13) arefound to be preparations allowing much higher transdermal absorbabilityas compared to those in the transdermal absorption patches inComparative Examples 2 and 3.

As can be seen from the test results in Test Examples 4-(3) and 4-(4),the preparations in Examples 6 to 13 each containing a transdermalabsorption enhancer exhibited higher transdermal absorbability thanthose in Examples 1 and 3 each containing no transdermal absorptionpromoting agent.

INDUSTRIAL APPLICABILITY

As described above, the present invention can provide a transdermalabsorption preparation containing free ropinirole and having favorabledrug permeability and high drug stability and contributes significantlyto the treatment of Parkinson's disease.

1. A transdermal absorption patch comprising: an acrylic-based adhesiveserving as an adhesive base, containing no cross-linking agent, havingno carboxyl group, and having a hydroxyl group or a pyrrolidone group;and free ropinirole added to the acrylic-based adhesive.
 2. Atransdermal absorption patch comprising: an adhesive base comprising anacrylic-based adhesive containing no cross-linking agent, having nocarboxyl group, and having a hydroxyl group or a pyrrolidone group; andfree ropinirole added to the adhesive base, the transdermal absorptionpatch further comprising a transdermal absorption promoting agent addedto the adhesive base.
 3. The transdermal absorption patch according toclaim 1, wherein the acrylic-based adhesive is a 2-ethylhexylacrylate/vinyl acetate/2-hydroxyethyl acrylate copolymer.
 4. Thetransdermal absorption patch according to claim 1, wherein theacrylic-based adhesive is a 2-ethylhexyl acrylate/vinylpyrrolidonecopolymer.
 5. The transdermal absorption patch according to claim 2,wherein the transdermal absorption enhancer is one or two or more kindsselected from triethyl citrate, glycerin, sorbitan monolaurate, oleylalcohol, and isopropyl myristate.
 6. The transdermal absorption patchaccording to claim 2, wherein the transdermal absorption enhancer is oneor two or more kinds selected from oleyl alcohol and isopropylmyristate.
 7. A transdermal absorption patch comprising: anacrylic-based adhesive serving as an adhesive base, containing nocross-linking agent, having no carboxyl group, and having a hydroxylgroup or a pyrrolidone group; and free ropinirole added to theacrylic-based adhesive, wherein, when a crystal seeding method (CSmethod) is preformed, a factor (C) representing a growth degree ofropinirole crystals in the adhesive satisfies (C)≦1,(C)=(b)/(a) [wherein, (a): a ratio of a total area of crystals of ascattered drug (a projected area from above: DSB) scattered in a certainarea (S) on a surface of the adhesive, i.e., DSB/S, immediately afterthe start of a test (immediately after the crystals of the drug arescattered), and (b): a ratio of a total area of the crystals of thescattered drug (the projected area from above: DSA) scattered in thecertain area (S) on the surface of the adhesive, i.e., DSA/S, aftercompletion of the test (10 days after the crystals of the drug arescattered)].
 8. The transdermal absorption patch according to claim 2,wherein the acrylic-based adhesive is a 2-ethylhexyl acrylate/vinylacetate/2-hydroxyethyl acrylate copolymer.
 9. The transdermal absorptionpatch according to claim 2, wherein the acrylic-based adhesive is a2-ethylhexyl acrylate/vinylpyrrolidone copolymer.
 10. The transdermalabsorption patch according to claim 3, wherein the transdermalabsorption enhancer is one or two or more kinds selected from triethylcitrate, glycerin, sorbitan monolaurate, oleyl alcohol, and isopropylmyristate.
 11. The transdermal absorption patch according to claim 4,wherein the transdermal absorption enhancer is one or two or more kindsselected from triethyl citrate, glycerin, sorbitan monolaurate, oleylalcohol, and isopropyl myristate.
 12. The transdermal absorption patchaccording to claim 3, wherein the transdermal absorption enhancer is oneor two or more kinds selected from oleyl alcohol and isopropylmyristate.
 13. The transdermal absorption patch according to claim 4,wherein the transdermal absorption enhancer is one or two or more kindsselected from oleyl alcohol and isopropyl myristate.
 14. The transdermalabsorption patch according to claim 5, wherein the transdermalabsorption enhancer is one or two or more kinds selected from oleylalcohol and isopropyl myristate.